Palladium-catalyzed regiodivergent hydroaminocarbonylation of alkenes to primary amides with ammonium chloride

Article abstract of DOI:10.1039/c7sc04054g

Palladium-catalyzed hydroaminocarbonylation of alkenes for the synthesis of primary amides has long been an elusive aim. Here, we report an efficient catalytic system which enables inexpensive NH₄Cl to be utilized as a practical alternative to gaseous ammonia for the palladium-catalyzed alkene-hydroaminocarbonylation reaction. Through appropriate choice of the palladium precursors and ligands, either branched or linear primary amides can be obtained in good yields with good to excellent regioselectivities. Primary mechanistic studies were conducted and disclosed that electrophilic acylpalladium species were capable of capturing the NH₂-moiety from ammonium salts to form amides in the presence of CO with NMP as a base.

Full text of DOI:10.1039/c7sc04054g

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Palladium-Catalyzed Regiodivergent Hydroaminocarbonylation of
Alkenes to Primary Amides with Ammonium Chloride
Bao Gao,a Guoying Zhang,a Xibing Zhou,a and Hanmin Huang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
Palladium-catalyzed hydroaminocarbonylation of alkenes for the synthesis of primary amides has long been an elusive
endeavor. Here, we report an efficient catalytic system which enables the inexpensive NH4Cl to be utilized as a practical
alternative to gaseous ammonia for the palladium-catalyzed alkene-hydroaminocarbonylation reaction. Through
appropriate choice of the palladium precursors and ligands, either branched or linear primary amides can be obtained in
good yields with good to excellent regioselectivities. Primary mechanistic studies were conducted and disclosed that
electrophilic acylpalladium species was capable of capturing the NH2-moiety from ammonium salts to form amides in the
presence of CO with NMP as a base.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Transition-metal-catalyzed hydroaminocarbonylation of
alkenes constitutes one of the most economical and efficient
methods for the construction of aliphatic amides from simple
Introduction
alkenes, CO and amines.10 Early studies on this field with Co, Ni,
Fe and Ru-catalysts required harsh reaction conditions and
Ammonia is among the least expensive industrial chemicals,
which has long been recognized as a cheap and ideal nitrogen-
source for the synthesis of N-containing molecules via C-N bond
formation reactions.1 However, the utility and abundance of
ammonia have not found frequent use in transition-metal
catalyzed reactions, although notable exceptions include
suffered from poor chemoselectivity.11 As
a means of
addressing the above synthetic problem, palladium-catalyzed
reductive
amination,2
hydroaminomethylation,3
hydroamination,4 allylic amination,5 aminocarbonylation,6 and
coupling of ammonia with aryl halides.7 Besides the general
technical complexities of using a gas, the potential reason for
the scarcity of reports on exploiting ammonia in metal-
catalyzed reactions may arise from its easy formation of
unreactive Lewis acid-base adducts with transition-metal owing
to its high basicity, small size and strong N-H bond.8 An
attractive and complementary approach would be to use
ammonium salts as surrogates of ammonia gas for establishing
transition-metal catalyzed reactions. In this respect, copper and
palladium-catalyzed C-N bond formation reactions between
aryl halides and ammonium salts have been established by
Chang and Hartwig.9 However, super stoichiometric amounts of
strong base were generally required in both of these systems to
form the metal-amide species from the in-situ released NH3,
leading to wasteful by-product generation. Therefore, design of
new and efficient protocols which are capable of directly
incorporating the nitrogen atom into the hydrocarbon from the
ammonium salts in the absence of base is highly desirable.
Scheme 1 Proposed hydroaminocarbonylation of alkenes to primary
amides with NH4Cl
hydroaminocarbonylation reaction, initiated by palladium-
hydride species, has been developed by Beller, Liu, our own
group and others.12,13 While the utility of this process has been
well demonstrated by the synthesis of various secondary and
tertiary amides, it is surprising to note that the related reaction
for the synthesis of aliphatic primary amides has never been
realized, although they are more valuable building blocks in the
synthesis of biologically active molecules and functional
materials.14 One obvious reason for discouraging the study of
this important unsolved synthetic problem is that the basic
ammonia is thought to be necessarily utilized in the related
hydroaminocarbonylation reaction, which is not only
incompatible with the acids typically utilized for palladium-
catalyzed hydroaminocarbonylation but also prone to forming
a.Department of Chemistry, and Hefei National Laboratory for Physical Sciences at
the Microscale, University of Science and Technology of China, Hefei, 230026, P.
R. China. E-mail: hanmin@ustc.edu.cn.
b.State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China
†Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
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unreactive Werner amine-complexes to deactivate the ammonium salts revealed that the transformationVwieawsAsrteicnlesOitnilvinee
catalysis.8 For the past several years, our group has been to the counter anion of the ammonium salts and found that
DOI: 10.1039/C7SC04054G
focused on the development of palladium-catalyzed alkene NH4Cl was a superb ammonium salt for this reaction (see SI).
hydroaminocarbonylation reactions.13 Crucial to the successful After identifying the optimized catalytic system for synthesis of
realization of these reactions is the formation of palladium- the branched amide 2a, we next sought to determine whether
hydride species to initiate the catalysis. Consistent with this the regioselectivity could be switched by changing the catalyst
concept, we found that hydroxylamine hydrochloride precursors and reaction conditions. This proved to be highly
(NH2OH•HCl) or alkylamine hydrochloride salts could act as co- successful: using PdI2 as a palladium source and Xantphos as the
catalysts or additives to generate palladium-hydride species via ligand, the regioselectivity was changed to an opposite direction,
oxidative addition with Pd(0), leading to establishing efficient favoring the linear amide 3a when the reaction conducted at
hydroaminocarbonylation reactions.13 In addition, Beller and 120 oC under 30 atm of CO (Table 1, entry 5). Encouraged by this
coworkers also demon-strated that the alkylamine result, we then checked different bidentate phosphine ligands
hydrochloride salts could be directly used as nitrogen source for with distinct bite angles, such as DPEphos, DPPF, and DPPB, and
the palladium-catalyzed hydroaminocarbonylation.12e Inspired found that Xantphos
by these results, we envisioned that the acidic ammonium salt
Table 1 Optimization of the reaction conditionsa
would be a surrogate of ammonia for establishing an efficient
catalytic hydroaminocarbonylation reaction to primary amides.
Herein, we report an efficient palladium-catalyzed
regioselective hydroaminocarbonylation of alkenes to prepare
aliphatic primary amides with NH4Cl as amino source. The
regioselectivity for this reaction is accomplished by the
appropriate choice of palladium-catalysts and reaction
conditions, and both of the linear and branched primary amides
can be constructed in high yields with good regioselectivities
(Scheme 1).
Results and discussion
Initially, to test whether the key palladium-hydride species
could be formed by the reaction of Pd(0) with an acidic
ammonium salt, the reaction of Pd(t-Bu3P)3 with NH4Cl was
investigated and monitored by NMR. After heating the mixture
of Pd(t-Bu3P)2 and NH4Cl in NMP at 120 °C for 30 min, a new
1
signal at -16.7 ppm appeared in the H NMR spectra, which
corresponded to the Pd-H resonance of HPd(t-Bu3P)2Cl.13c,15 As
prolonging the reaction time, the signal of Pd-H resonance
increased accordingly (see SI). These results convincingly
supported our hypothesis that the palladium-hydride species
can be produced by the reaction of Pd(t-Bu3P)2 and NH4Cl.
The above results intrigued us to study the catalytic hy-
droaminocarbonylation of alkenes with NH4Cl as nitrogen
source according to the proposed reaction pathway. On the
was the most efficient for giving the linear amide 3a in terms of
reactivity and selectivity (Table 1, entries 6-12). With this
catalyst set as optimal, we further screened other reaction
parameters to maximize the efficiency of the reaction. This led
to finding that the reaction time could be shortened to 4 hours
(Table 1, entry 13). Reducing the CO-pressure resulted in lower
reactivity but kept the same regioselectivity (Table 1, entries 13-
15). Interestingly, while the reaction can still be carried out
without Xantphos, only lower yield and regioselectivity were
observed, revealing that ligand is an important factor that
contributes to a satisfactory result (Table 1, entry 16). In
addition, we examined the effect of the solvent and observed
that other solvents provided unsatisfactory results in terms of
reactivity and selectivity.
basis
of
our
previous
studies
of
Pd-catalyzed
hydroaminocarbonylation reactions,13 the present reaction was
initially investigated with styrene (1a) and NH4Cl in the presence
of catalytic amount of Pd(t-Bu3P)2 under 30 atm of CO in NMP
at 120 oC. We were pleased to find that the reaction indeed did
proceed leading to the desired primary amides in 95%
combined yield with excellent regioselectivity for exclusively
giving the branched amide 2a as the main product (Table 1,
entry 1). Decreasing the pressure of CO to 10 atm led to lower
reactivity and selectivity (Table 1, entries 1-3). The simple
Pd(PPh3)4 could also deliver the desired amide 2a as main
product in excellent yield albeit with relatively lower
regioselectivity. With Pd(t-Bu3P)2 as catalyst, the reaction time
could be shortened to 15 h. Further evaluation of various
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With the optimized reaction conditions in hand, we first 2p in 45% yield with a tolerating ketone group. This
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DOI: 10.1039/C7SC04054G
examined the substrate scope for the synthesis of branched transformation indicated that the reaction system is amenable
amides under the catalysis of Pd(t-Bu3P)2, and the results are to functionalization and modification of complex alkenes
summarized in Table 2. A variety of styrenes bearing mono- bearing the skeleton of natural products, and show high
substitutents on the aryl ring were initially surveyed. Both potential applications in biological evaluation. Unfortunately,
electron-donating and –withdrawing groups were compatible aliphatic alkenes were less reactive and only 30% yield was
with this transformation, and a series of functional groups, such obtained for allylbenzene when the reaction was conducted
as ether, halogen and ketone, were tolerated to give the desired under 50 atm of CO for 24 h, which may be attributed to faster
products 2a-2j in moderate to excellent yields with good to β-hydride elimination and slower CO insertion for aliphatic
excellent regioselectivities. The structure of 2e was confirmed alkenes.
by X-ray crystallographic analysis.16 For the styrenes
Table 3 Substrate scope for linear amide synthesisa
Table 2 Substrate scope for branched amide synthesisa
with disubstituents on the aryl ring, including 3,4-
dichlorostyrene and 2,6-dimethylstyrene, the reactions
proceeded smoothly to generate 2k and 2l in good yields with
good selectivities. The reactions of 2-vinylnaphthalene and 1-
vinylnaphthalene delivered 2m and 2n in 71% and 68% yields,
Inspired by the above results, we turned our attention to the
respectively. In addition, the reaction of 9-vinylphenanthrene
investigation of the substrate scope for the synthesis of primary
also provided product 2o in 68% yield with good regioselectivity.
linear amides under the catalysis of PdI2/Xantphos in the
Hydroaminocarbonylation of estrone derivative alkene bearing
presence of 30 atm CO pressure (Table 3). To our delight, a
a steroid scaffold was also conducted to produce linear amide
range of styrenes and vinylnaphthalenes were also suitable to
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react with NH4Cl and CO under the optimized reaction derivative was employed to deliver linear amide 2p in 65% yield
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DOI: 10.1039/C7SC04054G
conditions, and a series of functional groups, such as ether, under the catalysis of Pd(COD)Br2/Xantphos system. The solid
halides and ketone, could survive to give the desired linear structure of 3h was further unambiguously confirmed by X-ray
amides 3a-3l in 67-86% isolated yields with good crystallographic analysis.16
regioselectivities. Notably, the regioselectivity was changed
To further examine and expand the scope of the reaction, the
dramatically depending on the substitution. For instance, while use of disubstituted alkenes was considered, as they allow
the reaction took place high selectively with substrates bearing access to considerably more structurally diverse amides but
a methyl group at the ortho-position (Table 3, entry 4), the pose a greater challenge. Indeed, the reaction of α-methyl
selectivity was lower when it was located at the para- or meta- styrene failed to yield the desired amide with low conversion
under the catalysis of Pd(t-Bu3P)2 or PdI2/Xantphos system.
Table 4 Substrate scope for disubstituted alkenea
However, a slightly change from the PdI2 to the Pd(COD)Br2 led
to the successful hydroaminocarbonylation, allowing for
significant expansion of the scope (Table 4). Under these
reaction conditions, the desired reaction was amenable to a
broad range of α-methyl styrenes, 2-(prop-1-en-2-
yl)naphthalene as well as 2-(prop-1-en-2-yl)thiophene, giving to
a range of primary amides in good to excellent yields with
complete regioselectivities (Table 4, entries 1-9). Aside from
simple α-methyl styrenes, many other α-substituted aromatic
alkenes with different substituents at the α-position were also
compatible with this novel reaction, generating the
corresponding primary amides in 51% to 69% yields (5j-5l). The
structure of the amide 5l was also confirmed by single-crystal X-
ray crystallographic analysis.16 In addition, cyclic alkenes, such
as norbornene and cyclohexene could be smoothly transferred
to the corresponding primary amides 5m in 77% and 5o in 79%
yield, respectively. Notably, the 1,5-cyclooctadiene was also
readily converted to the desired primary amide 5n in good yield
with one double bond remained. Interestingly, double
carbonylation was occurred when 3-bromocyclohex-1-ene was
subjected to the present reaction conditions, providing the
corresponding imide 5p in 65% yield.
Scheme 2 Synthetic applications
position (Table 3, entries 2-3). Similar excellent
regioselectivities and good yields were observed for the
The hydroaminocarbonylation of simple ethylene to pro-
reactions of 2-chlorostrylene, 2,6-dimethylstyrene and 1-
pionamide
6 with NH4Cl on a 20 mmol scale was successfully
vinylnaphthalene (Table 3, entries 9, 11 and 14). In addition to
aryl alkenes, the simple unactivated aliphatic alkenes are also
suitable substrates for this reaction to give the corresponding
linear amides in good yields and regioselectivities (Table 3,
entries 15-19). Importantly, this reaction is not limited to simple
aliphatic alkenes. For instance, functionalized aliphatic alkenes,
bearing chlorine, bromine, ether, ester and phthalimide, could
be successfully converted to the desired linear amides 3t-3y in
satisfactory yields and good regioselectivities. An estrone
realized in the presence of 0.01 mol% of Pd(t-Bu3P)2 (18% yield
based on NH4Cl, TON 1800). In addition, with
Pd(CH3CN)2Cl2/Xantphos as the catalyst, the secondary amide
N-propionylpropionamide can be effectively assembled in 95%
yield. Furthermore, the 15N-labeled primary amide (2m) was
obtained when 15NH4Cl was utilized as coupling partner, which
provides a convenient method to incorporate 15N into amides.
Finally, to demonstrate scalability, the reaction was performed
=
7
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on preparative scale (15 mmol) with 1-(tert-butyl)-4- CO was essential for facilitating the process.18a The formation of
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vinylbenzene 1e as a substrate. The target reaction proceeded branched amide 2a from the linear acylpalladium
smoothly at a lower catalyst loading (0.1 mol%), affording the that the CO-deinsertion/insertion,
desired branched primary amide 2e in 81% yield with excellent elimination/hydropalladation were occurred and reversible.
regioselectivity (Scheme 2, eq 4).17
However, the lower selectivity for getting the branched amide
To better understand the mechanism, a series of control 2a from the linear acylpalla-dium indicated that the reverse
DOI: 10.10399/Cs7uSCg0g4e0s5t4eGd
β-hydride
9
experiments were performed. Initially, the HPd(t-Bu3P)2Cl was reaction is slow under the reaction conditions, which was
prepared according to the reported method and utilized as a further supported by the deuterium studies, in which only
catalyst for the standard reaction.15 As expected, excellent partial D-scrambling was observed (Scheme 3, eqs 7 and 8). As
reactivity and selectivity were observed for the desired reaction expected, the acylpalladium
9 can catalyze the present
(Scheme 3, eq 1), suggesting the plausible intermediacy of the hydroaminocarbonylation to give the desired product in high
palladium-hydride in the catalytic cycle. Moreover, the putative yield under the standard conditions, suggesting the plausible
acylpalladium intermediate
3-phenylpropanoyl chloride
The structure of complex
9
8
was prepared via the reaction of intermediacy of acylpalladium
with Pd(t-Bu3P)2 (Scheme 3, eq 2). eq 5). Further control experiments disclosed that the desired
was confirmed by X-ray amide 3a could be facilely produced by the reaction of acid
with NH4Cl in NMP at 120 oC (Scheme 3, eq 6).19 This
9 in the catalytic cycle (Scheme 3,
9
crystallography.16 This complex adopts a monomeric T-shaped chloride
8
geometry at palladium, with acyl ligand trans to the open result together with previous reports18 that acid chloride could
coordination site, as has been reported for related aroyl- be generated by the reductive elimination of aroyl palladium
palladium complexes.18 With the acylpalladium complex
9
in complexes in the presence of CO suggested two possible
hand, we proceeded to execute a set of experiments to pathway for the formation of amide from the acylpalladium
elucidate whether the acylpalladium could be (1) the NH4Cl directly reacts with acylpalladium and (2) acid
chloride was formed firstly from the acylpalladium , which
9
:
9
9
9
then reacted with NH4Cl to generate the desired amide. In both
of which NMP may function as base to the capture the produced
HCl (see Supporting Information).
Fig. 1 Kinetic plots of reaction in eq 3 [acylpalladium 9 (0.2 mmol),
NH4Cl (0.4 mmol), CO (10 atm), NMP (10 mL) at 120 oC] and reaction
in eq 6 [8 (0.2 mmol), NH4Cl (0.4 mmol), NMP (10 mL) at 120 oC].
To distinguish the two possibilities, kinetic reaction profiles
for the two stoichiometric reactions of NH4Cl with acylpalladium
complex 9 (eq 3) or acid chloride 8 (eq 6) were investigated. The
Scheme 3 Preliminary mechanistic studies
rate of reaction in eq 3 was faster than that of reaction in eq 6
(Figure 1). In principle, if a reaction is composed of multiple
steps, the observed global kinetic rate should be slower than
the rate of each steps, or at least equal to the slowest step if it
exists. If the desired amide generated from the acid chloride, eq
6 should be part of the reaction pathway, and the observed rate
of reaction in eq 6 should be faster or at least equal to that of
reaction in eq 3. However, opposite results were gained, which
excluded acid chloride as an intermediate in the reaction of eq
3. and supported that the desired amide was most likely
converted to amide and how the NH2-moiety was installed into
the desired amide from NH4Cl. The treatment of acylpalladium
9
with two equivalents of NH4Cl in the presence of CO in NMP
at 120 oC afforded the linear amide 3a and branched amide 2a
in good yields (Scheme 3, eq 3). However, no desired amide was
detected, but styrene was formed when the same reaction was
conducted in the absence of CO under other identical reaction
conditions (Scheme 3, eq 4). These results indicated that the
acylpalladium
9 could be converted to the desired amides and
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generated by the direct reaction of NH4Cl with acylpalladium NH4Cl into the amide were provided. These results suggested
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complex in NMP.
that the reaction proceeded through foDrmOIa: t1i0o.1n03o9f/Cp7aSlCla0d40iu5m4G-
hydride species generated by oxidative addition of NH4Cl to
Pd(0) and the acylpalladium species was capable of directly
capturing the NH2-moiety from the ammonium salt under the
assistance of CO in NMP, which has promise as a valuable
strategy for utilizing ammonium salts as practical alternatives to
gaseous ammonia in a variety of C-N bond-forming manifolds.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21672199 and 21702197), CAS
Interdisciplinary Innovation Team, the Fundamental Research
Funds for the Central Universities and the Anhui provincial
Natural Science Foundation (1708085MB28).
Fig. 2 Plausible reaction mechanism
While a precise reaction mechanism is not yet clear at the
present stage, the most plausible mechanism in line with our
experimental results and previous reports is illustrated in Figure
2. First, an oxidative addition of NH4Cl to Pd(0) would produce
the key palladium-hydride species. Reversible coordination and
insertion of alkene into the palladium-hydride yielded a Pd-alkyl
Notes and references
1
(a) J. R. J. LeBlanc, S. Madhavan, R. E. Porter and P. Kellogg,
Encylopedia of Chemical Technology, 2nd edn, Vol. 2 (Wiley,
1963); (b) Y. Aubin, C. Fischmeister, C. M. Thomas and J.-L.
Renaud, Chem. Soc. Rev., 2010, 39, 4130; (c) J. L. Klinkenberg
and J. F. Hartwig, Angew. Chem., Int. Ed., 2011, 50, 86; (d) J.
Kim, H. J. Kim and S. Chang, Eur. J. Org. Chem., 2013, 3201; (e)
H. Kim and S. Chang, Acc. Chem. Res., 2017, 50, 482.
intermediate
A
or
C, which underwent CO insertion to form
B
and
or
D
D
. Consequently, the resultant acylpalladium species
B
directly reacted with NH4Cl in the presence of CO to generate
the desired amides. The key palladium-hydride species was
simultaneously generated to enter the next catalytic cycle and
the released HCl might be trapped by NMP solvent (see SI) to
finish the catalytic cycle. The regioselectivity was found to be
highly influenced by the ligand used and the branched amide
was exclusively formed for the aromatic alkenes with
monodentate ligands. The phenyl group could stabilize
palladium intermediate C via delocalization to form η3-benzyl
palladium-complex.20 The t-Bu3P appeared to be highly
favorable to such stabilization due to its ability to create
coordinatively unsaturated palladium complex arisen from its
2
(a) T. Gross, A. M. Seayad, M. Ahmad and M. Beller, Org. Lett.,
2002, 4, 2055; (b) S. Ogo, K. Uehara, T. Abura and S. Fukuzumi,
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4
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B. Zimmermann, J. Herwig and M. Beller, Angew. Chem., Int.
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6
(a) X.-F. Wu, H. Neumann and M. Beller, Chem. Asian. J., 2010,
size and donor ability, thus facilitating the formation of
the subsequent migratory insertion process to predominately
give branched amide . In contrast, the bidentate Xantphos
appeared to favor linear palladium intermediate likely due to
C and/or
5
, 2168; (b) X.-F. Wu, J. Schranck, H. Neumann and M. Beller,
ChemCatChem, 2012,
4, 69; (c) X.-F. Wu, H. Neumann and M.
2
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6041.
,
A
the steric hindrance in the corresponding palladium catalyst
created by the double bounded diphosphine ligand,
consequently facilitating the formation of linear amide.
7
(a) Q. Shen and J. F. Hartwig, J. Am. Chem. Soc., 2006, 128
,
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Conclusions
8
9
In summary, we have successfully developed a practical
palladium-catalyzed protocol for the synthesis of primary
aliphatic amides via hydroaminocarbonylation of alkenes with
NH4Cl as a surrogate of ammonia in the presence of CO. A wide
range of linear or branched primary amides have been obtained
in high yields with good to excellent regioselectivities, which
represents the first example of the direct conversion of NH4Cl
to primary aliphatic amides in the absence of base. Apart from
the synthetic value of this transformation, important
mechanistic evidences regarding the origin of the palladium-
hydride and the pathway for incorporation of NH2-moiety from
10 For recent reviews on synthesis of amides via carbonylation,
see: (a) X.-F. Wu, H. Neumann and M. Beller, Chem. Soc. Rev.,
2011, 40, 4986; (b) X.-F. Wu, H. Neumann and M. Beller, Chem.
Rev., 2013, 113, 1; (d) X.-F. Wu, X. Fang, L. Wu, R. Jackstell, H.
Neumann and M. Beller, Acc. Chem. Res., 2014, 47, 1041.
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Chemical Science
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Journal Name
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16 CCDC 1515391 (2e), 1515399 (3h), 1515405 (5l) and 1552470
(
9
) contain the supplementary crystallographic data for this
paper. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
17 The utility of this catalytic reaction has been further
demonstrated by streamlined synthesis of ibuprofen, nitriles
and 3,4-dihydroquinolin-2(1H)-one from simple alkenes and
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19 No reaction occurred when the reaction was conducted in
many other solvents such as toluene, CH2Cl2, THF, 1.4-dioxane
and hexane, suggesting the basic NMP is essential for
facilitating the reaction by capturing the released HCl (see
Supporting Information for detail).
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